Lactones of the saturated and unsaturated cyclopentanopolyhydrophenanthrene series and process of preparing same



latented Apr. 23, 1946 U IT D STATE s PATENT OFFICE LACTONES OF THE SATUBATED AND UN- SATUBATED CYCIDPENTANOPOLYHY- DBOPHENANTHRENE SERIES AND PROC- ESS F PREPARING SAME Leopold Ruzicka, Zurich, Switzerland, asslgnor to Ciba Pharmaceutical Products, Incorporated. Summit, N. ,L, a corporation of New Jersey No Drawing. Application April 29, 1942, Serial No.

' 441,034. In Switzerland June 10, 1941 11 Claims. (c1. zoo-239.5)

This invention relates to the manufacture of lactones of the saturated and unsaturated cyclopentanopolyhydrophenanthrene-series by con- T densing hydroxy methylene derivatives of the general formula I .wherein one of the two R's stands for a radical ethrifled hydroxyl group, with a functional derivative of a halogen fatty'acid, such as an aor ,a-halogenated fatty acid ester, amide or nitrile, and if desired subjecting the condensation product to the action of hydrolyzing and lactonizing agents or to a re-esterifying treatment and/or a treatment for splitting oil! water.

The parent materials can be obtained for example from side chains ketones'or aldehydes-of the cyclopentanopolyhydrophenanthrene series, such as A-3-acetoxy-pregnene-ZO-one, A -3-hydroxy 21 methyl pregnene-20-one, A -3-hydroxy-pregnene-zl-al, A -3-acetoxy-2l-methylpreg'nene-ZO-one or 3:7 lz-triacetoxy-pregnane- 20-one, in a manner known in itself by condensation with functional derivatives of formic acid or oxalic acid, for example in the presence of alkali metals or their alcoholates or amides. In most cases, the hydroxymethylene compounds thus obtained need not be purified, and they can be converted directly into their esters or ethers, preferably in the form of their enol salts.

The condensation with halogen fatty acid derivatives may be efiected in known manner by means of metals, such as zinc or magnesium, in a suitable inert solvent, for instance benzene, toluene, dioxane or ether. Lactonization generally occurs during the condensation and also frequently a partial elimination of water. when worked up as mixtures. Thus if desired the condensation product may be subjected to the known treatments for eliminating water, of which distillation or sublimation under diminished pressure has proved especially useful,

if desired after admixture with surface-active substances, forinstance aluminium oxide, silica gel, active carbon, fullers earth or with an anhydrous salt, for instance copper sulfate. when the substituent X has been a free or a functionally moderated carboxylic acid group, such as an esteriiled oarboxylic acid group, a nitriie or T amide group, the products obtained may be subsequently subjected to the action of decarboxylating means, for instance heat. For isolating pure components the mixture produced of lactones may be treated in the usual manner, for instance by fractional crystallization or by chromatographic adsorption analysis. 7

The described reactions can be illustrated, for

example as follows:

CH, CH "5; OHGH -co 011-0. CIL-OAc m Jan. COOClHI on, em on 011 cqcm cbcn i D Etta F; d t) If in the above schedule for example the hydroxymethylene compound I is subjected for instance to a catalytic hydrogenation, a mono unsaturated lactone (for example of the Formula IV) is obtained as final product. The treatment with reducing agents, however, may also take place at any other stage of the process.

The products obtained by this process are or more membered saturated hydroxylactones or unsaturated lactones of the cyclopentanopolyhydrophenanthrene-series. They may possess between the lactone ring and the cyclopentanopolyhydrophenanthrene nucleus an aliphatic radical, for instance an alkylene group. The six-membered unsaturated lactones represent i-pyrones carrying for'example in 6-, p'- or po ition a 'radical which contains the cyclopentanopolyhydrophenanthrene frame and which, furthermore, may be substituted by a hydrocarbon radical, such as alkyl, and also partially hydrogenated.

The following examples illustrate the invention but are not to be regarded as limiting it in any way:

Example 1 8.5 grams of A=-8-acetoxy-2l-acetoxymethylenepregnene-20-one of the formula cm cm cn'looo (prepared for example by the action of amylformate and potassium methylate in a benzene solution on A -3-acetoxy-pregnene-20-one and subsequent acetylation by means of acetylchloride) are dissolved in benzene, mixed with 2 grams of zinc spangles and heated with 4.8 grams of ethyl bromoacetate until the reaction is complete. The reaction mixture is now largely con- I centrated, the residue diluted with absolute alcohol, the solution filtered to remove the zinc mud and then poured into dilute hydrochloric acid.

The reaction products which have precipitated are boiled for a short time with little alcohol containing hydrochloric acid and then suctionfiltered. The products are further purified by chromatographic adsorption. As main product there is obtained A *-3-acetoxy-21-hydroxymethyiene-nor-choladienic acid lactone (5' [A 3-acetoxyandrostenyl (17)] pentadienolide) of the formula CH1 CH CHaGOO In addition there is also formed A -Ii-hydroxy-21-hydroxymethylene-nor-choladienic acid lactone of the formula CH; CHI

assessor or its S-acetate may be obtained in analogous manner.

When using an a-halogenpropionic ester or an a-halogenpropionic nitrile or -diethyl amide instead of a halogen acetic ester, there is obtained a'-methyl-p- [A acetoxy androstenyl (1'7) 1- pentadienolide of the formula OH; on. cm 4,

0 oo ..l l

cfi

CHsCOO Example 2 5 grams of the condensation mixture obtained by the action of A =-3-acetoxy-17il'l -oxo-propyll-androstene with oxalic ester and subsequent acetylation, are caused to react in benzene-dioxane with 10 grams of activated zinc spangles and 15 grams of ethyl bromoacetate. When the reaction has ceased, the reaction mixture is diluted with absolute alcohol and the solution is filtered to remove the unchanged zinc. Some concentrated hydrochloric acid is added to the solution and the alcohol is largely concentrated. The reaction products are taken up in ether, washed thoroughly with water and subjected to a distillation in a high vacuum. The feebly colored distillate is purified by chromatographing or recrystallizing. There is obtained TEA -3- hydroxy androstenyl-(l'l) ]-fl'-methyl-pentadienolide (A -3:21-dihydroxy-22-methylcholatrienic acid lactone) of the formula In addition there is formed p[A -3-hydroxy-21- nor-pregnenyl-(20)l-pentadienolide of the for- The reaction scheme of the foregoing example may be graphically represented as follows:

CH: CH!

wherein one of the two R's is a radical containing the cyclopentanopolyhydrophenanthrene rinl JCIIa-C O-GH:

' Hi C O 0 /Oxallc acid ester\ 1 acetylatlon CHI CH: CH3 0 CH; CE;

I i -cm-co H t ooocrn oo 0 cm c mccoo- Zn Zn Ethyl bromacetate Ethyl bromacetete' CHI 0H cm OH; CH: cm i (6 on, OH:-- oooa CH 5 O O R 3H (5 O C CH: a) 00cm c H:CCOO HzCCOO\/\/ Cone. HO] Cone. H01

(saponiflcation ringc1osure (saponiflcation ring-closure splitting of! water) splitting ofl water) CH: cm CH:

6 -CH1C oo on oo J O /Y C H0 H0 What I claim is:

1. A process for the manufacture of lactones of the saturated and unsaturated cyc1opentano-' polyhydrophenanthrene series, comprising treating a hydroxy methylene derivative of the general formula R-C O-C-R XC-Y wherein one of the two R's is a radical containing the cyclopentanopolyhydrophenanthrene ring structure, the other R is a member of the group consisting of hydrogen and a hydrocarbon radical, X stands for a member of the group consisting of hydrogen and carboxylic acid ester, amide v and nitrile groups, and Y is a member of the group consisting of a free and esterified hy- 1- droxyl group, with a member of the group consisting of aand Si-halogenated fatty acid esters, amides and nitrlles.

2. A process for the manufacture of lactones of the saturated and'unsaturated cyclopentanopolyhydrophenanthrene series, comprising treating a hydroxy methylene derivative of the general formula R-co-o-R structure, the other R. is a member of the group consisting of hydrogenand a hydrocarbon radical, X stands for a member of the group consisting of hydrogen and carboxylic acid ester, amide and nitrile groups, and Y is a member of the group consisting of a free and esterifled hydroxyl group, with an ester of an u-halogen fatty acid.

3. A process for the manufacture of lactones of the saturated and unsaturated cyclopentanopolyhydrophenanthrene series, comprising treating a hydroxy methylene derivative of the general formula RCOC-R XT'C-Y wherein one of the two R's is a radical containing the cyclopentanopolyhydrophenanthrene ring structure, the other R is a member of the group consisting of hydrogen and a hydrocarbon radical, X stands for a member of the group consisting of hydrogen and a carboxylic acid ester,

amide and nitrile groups, and Y is a member of the group consisting of a free and esterifled hydroxyl group, with ethylbromacetate.

4. A process for the manufacture of lactones oi the saturated and unsaturated cyclopentanopolyhydrophenanthrene series, comprising treating a hydroxy methylene derivative of the general formula R-OO-O-R wherein one of the two R's is a radical containing the cyclopentanopolyhydrophenanthrene ring structure, the other R. is a member of the group consisting of hydrogen and a hydrocarbon radical, X stands for a member of the group consisting of hydrogen and carboxylic acid ester, amide and nitrile groups, and Y is a member of the group consisting of a free andesterifled hydroxyl group, with a member of the group consisting of ozand fi-halogenated fatty acid esters, amides and nitriles, and then subjecting the-condensation product to a process for eliminating water. 5. A process for the manufacture of lactones of the saturated and unsaturated oyclopentanopolyhydrophenanthrene series, comprising treating a hydroxy methylene derivative of the general formula R-OO--OB wherein one of the two R's is a radical containing the cyclopentanopolyhydrophenanthrene ring structure, the other R is a member of the group consisting of hydrogen and a hydrocarbon radical, X stands for a member of the group consisting of hydrogen and carboxylic acid ester,

amide and nitrile groups, and Y is a member I, of the group consisting of a free and esterified hydroxyl group, with a member of the group consisting of czand ,B-halogenated fatty acid esters, amides and nitriles, and then subjecting the condensation product to the action of members of the group consisting of re-esterifying, hydrolizing and lactonizing agents and decarboxylating means.

6. A process for the manufacture of lactones of the saturated and unsaturated cyclopentanopolyhydrophenanthrene series, comprising treating a hydroxy methylene derivative of the gen eral formula a-co-c-n wherein one of the two R's is a radical containing the cyclopentanopolyhydrophenanthrene ring structure, the other It is a member of the group consisting of hydrogen and a hydrocarbon radical, X stands for a member of the group consisting of hydrogen and carboxylic acid ester, amide and. nitrile groups, and Y is a member of the group consisting of a free and esterified hydroxyl group, with a member of the group consisting of czand p-halogenated fatty acid esters, amides and nitriles, subjecting the condensation prodnot to the action of members of the group cansisting of re-esterifying, hydrolyzing and lactonizing agents and decarboxylating means. and then to a process for eliminating water.

I. A process according to claim 1, wherein is carried out as additional step a treatment with a hydrogenating agent.

wherein R represents the aforesaid radical and X represents a hydrocarbon radical.

9. The compounds selected from the group consisting of a-pyrones and partially hydrogenated a-pyrones which are substituted by a radical containing the cyclopentanopolyhydrophenanthrene ring structure and which contain a hydrocarbon radical substituent in one of the positions a and ,8 on the lactone ring, the latter being otherwise free from substituents, and the linkage between the flrst-mentioned radical and the lactone ring being a direct carbon-to-carbon linkage.

l0. a-PYIODBS which are substituted in -y'-position by a radical containing the cyclopentanopolyhydrophenanthrene ring structure and which contain a hydrocarbon radical substituent in one of the positions a and p on the lactone ring, the latter being otherwise free from substituents, and the linkage between the first-mentioned radical and the lactone ring being a direct carbon-tocarbon linkage.

11. The -y'-substituted a-pyrone of the formula LEOPOLD RUZICKA.

Certificate of Correction Patent No. 2,398,861. April 23, 1946.

LEOPOLD RUZICKA It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: Page 3, second column, approximately line 30, Example 2, for the right-hand portion of the formula reading A read v DOCK: OOCOH and that the said Letters Patent should be read with this correction therein that th same may conform to the record of the case in the Patent Office.

Signed and sealed this 30th day of July, A D. 1946.

LESLIE FRAZER,

First Asszstant Commissioner of Patents. 

